Dr Arun Aggarwal

MD
Epidemiology
 Worldwide prevalence of 7-11%

Lovell RM, Ford AC. Global Prevealence of and Risk Factors for Irritable Bowel Syndrome:
a Meta-analysis. Clinical Gastroenterology and Hepatology 2012:10(7); 712-21.
Epidemiology and Disease Burden
 Prevalence in North America about 7-15%
 F:M ratio 1.5-3:1
 Over $20 billion in annual direct and indirect costs
 Estimated 3.6 million physician visits for IBS in the
U.S. annually
 Associated with decreased quality of life
Andrews EB , Eaton SC , Hollis KA et al. Prevalence and demographics of irritable bowel
syndrome: results from a large web-based survey. Aliment Pharmacol Ther 2005;22: 935–42.
Survey of >31,000 patients
 7 % prevalence for IBS
 prevalence increased as income decreased
 9.0% (CI: 8.1–10.0) among individuals with an annual
income <$20,000 vs. 5.2% (CI: 4.7–5.8) in the highest
income group
 Unemployed individuals had a higher prevalence of IBS
(10.0%, CI: 8.9–11.1) than those who were employed
(5.9%; CI: 5.6–6.3)

Andrews EB , Eaton SC , Hollis KA et al. Prevalence and demographics of irritable bowel syndrome:
results from a large web-based survey. Aliment Pharmacol Ther 2005;22: 935–42 .
Diagnosis
 Manning criteria 1978
 Rome I 1990
 Rome II 1999
 Rome III 2006
 Rome IV ????
Manning Criteria 1978

Manning AP, Thompson WG. Towards positive diagnosis of the irritable

bowel. BMJ 1978;2:653-4.
Manning criteria
 Pain relieved with defecation
 More frequent stools at onset of pain
 Looser stools at onset of pain
 Visible abdominal distention
 Passage of mucus more than 25% of the time
 Sensation on incomplete evacuation more than 25% of
the time
Kruis score

Kruis W, Thieme C, Weinzierl M, et al. A diagnostic score for the irritable bowel
syndrome. Its value in the exclusion of organic disease. Gastroenterology 1984;87:1–7.
Rome III
 Recurrent abdominal pain or discomfort at least 3 days
per month in past 3 months and at least 2 other
features:
 Improvement with defecation
 Onset associated with change in stool frequency
 Onset associated with change in stool form
(appearance)
IBS Classifications

Feldman M, Friedman FS, et al. Irritable Bowel Syndrome. Gastroenterology and Liver
Disease Ninth Edition 2010(118)2091-2104.
Other complaints
 Abdominal bloating  Dysmenorrhea
 Increased flatulence  Impaired sexual function
 Nausea  Dyspareunia
 Reflux  Urinary
 Dysphagia frequency/urgency
 Non-cardiac chest pain  Fibromyalgia symptoms
Other considerations
 Celiac disease
 Lactose intolerance
 SIBO
 IBD
 Neoplasia
 Microscopic colitis
 Infections
 Chronic pancreatitis
Alarm features
 Weight loss
 Iron deficiency anemia
 Rectal bleeding
 Nocturnal symptoms
 Family history of selected organic diseases including
colorectal cancer, IBD and celiac disease
ACG Recommendations (2009)
 “Routine diagnostic testing with complete blood count,
serum chemistries, thyroid function studies, stool for
ova and parasites, and abdominal imaging is not
recommended in patients with typical IBS symptoms
and no alarm features because of a low likelihood of
uncovering organic disease.”
 “Routine serologic screening for celiac sprue should be
pursued in patients with IBS-D and IBS-M”

Brandt LJ, Chey WD, et al. An Evidence-Based Systematic

Review on the Management of Irritable Bowel Syndrome. The
Am J Gastroenterology 2009; Volume 104 supplement 1.
Diagnostic tests
 Diarrhea:
 Serum IgA tissue transglutaminase (IBS-D/M)
 Colonoscopy/sigmoidoscopy with biopsies
 Consider stool studies (Giardia, O&P)

 Constipation:
 AXR
 Consider colonoscopy/sigmoidoscopy
 In 2006, NIH disbursed $18,787,710 for IBS-related
research
Pathophysiology
 Psychosocial dysfunction
 Motility
 Hypersensitivity
 Bacterial overgrowth
 Microflora alteration
 Intestinal Inflammation
 Postinfectious
 Food Sensitivity
 Genetics
Afferent pathways

Costa M, Glise H et al. Summary. Gut 2004;53(Suppl II):ii22–ii25.

Visceral Hypersensitivity
 Balloon distention in intestine
 Pain reported at lower volumes in IBS patients; suggests
visceral hypersensitivity
 Increased reporting of pain rather than increased
neurosensory sensitivity (Dorn SD. Gut 2007)
 Discrimination index: measures neurosensory sensitivity
(physiological) based on ability to discriminate between two
stimuli of similar, yet distinct, intensities.
 Report criterion: measure of tendency to label any stimuli as
weak vs intense, independent of the actual stimulus intensity
 Report criterion (B)

Discrimination index p(A)

Dorn SD, Palsson OS. Increased colonic pain sensitivity in irritable bowel syndrome is the result of an
increased tendency to report pain rather than increased neurosensory sensitivity. Gut 2007;56:1202–09.
Brain Imaging and
Visceral Hypersensitivity
 Meta-analysis of 16 fMRI or PET studies from 1997-
2010
 Brain activation in IBS vs controls during rectal ballon
distention
 Inconclusive findings with no significant difference in
any region of the brain
 Further studies with standardization of protocol
recommended
Sheehan J, Gaman A, et al. Pooled analysis of brain activity in irritable bowel syndrome and
controls during rectal balloon distension. Neurogastroenterol Motil (2011) 23:336–e158.
Abnormal Motility
 Present in some patients
 Increased frequency/irregularity of intestinal
contractions
(Simren M, et al Dig Dis Sci 2000; Schmidt T, et al Scand J Gastroenterol
1996)
 Prolonged transit-time in IBS-C
(Agrawal, A, Houghton LA, et al. Am J Gastro 2009)
 Diarrhea may be due to enhanced gastrocolic response, rectal
hypersensitivity, or increased high-amplitude propagated contractions
 12 IBS patients
(minimum 4 BM’s
daily with negative
colon biopsies); 10
controls
 Exaggerated response
with increased high
amplitude
propogating
contractions to meal
ingestion and to
cholecystokinin
octapeptide in IBS-D.

Chey WY, Jin HO et al. Colonic

motility abnomrality in patients
with irritable bowel syndrome
exhibiting abdominal pain and
diarrhea. Am J Gastroenterol
2001;96:1499-1506.
Post-infectious IBS
 Associated with bacterial, viral, protozoan and
helminth infections
 10-30% incidence of IBS after recovery from proven
bacterial enteritis
 Risk factors: younger age, prolonged fever, anxiety,
depression
 Bile malabsorption has been reported
 Increased seratonin from enteroendocrine
cells/lymphocytes shown after Campylobacter enteritis
Findings suggest low-grade
inflammation/immune activation
 Findings mostly in IBS-D and post-infectious IBS
 Increased lymphocytes in colon and small intestine
 Increased mast cells in jejunum, terminal ileum and colon
 Proximity to colon neurons correlated with symptoms in one
study
 Increased fecal serine-protease levels in IBS-D
 Can activate protease-activated receptors (PARs) which may
damage tight junctions and increase intestinal permeability
 Increased mRNA levels of pro-inflammatory interleukin-1
β in rectal mucosa after post-infectious IBS
 Lower colonic mucosal mRNA expression of anti-
inflammatory cytokine IL-10 in females with IBS
Study of 477 cases, 1492 case-relatives, 297
controls, and 936 control-relatives

Saito YA. The Role of Genetics in IBS. Gastroenterol Clin N Am 2011(40):45–67.

Genetics
 Polymorphisms of the seratonin transporter gene may
be associated with IBS
 altered seratonin reuptake efficacy may affect peristalsis
 Studies of twins (dizogotic and monozogotic) show
contradictory findings.
IL 10 Genotypes Study
230 IBS patients vs 450 controls
 Significantly fewer IBS patients with the high producer
(-1082*G/G) genotype (IBS v controls: 21% v 32%;
p=0.003)
 Increased proportion of patients being positive for the
A allele, being either the low producer genotype -
1082*A/A or the heterozygous -1082*G/A (IBS v
controls: 79% v 68%; p=0.004).

Gonsalkorale WM, Perrey C. Interleukin 10 genotypes in irritable bowel

syndrome: evidence for an inflammatory component? Gut 2003;52:91–93.
Alteration in Fecal Microflora
 Both an increase and decrease of variation
have been proposed to characterize the GI microbiota
in IBS
 Greater alterations seen in IBS-D than IBS-C
 Studies performed with specific quantitative PCR or
with holistic 16S rDNA sequencing
 Decreased Clostridium coccoides and some
Bifidobacterium groups
 Decrease Lactobacilli has been detected in IBS-D
Salonen A, de Vos WM et al. Gastrointestinal microbiota in irritable bowel
syndrome: present state and perspectives. Microbiology (2010), 156, 3205–15.
Molecular analysis of fecal microbiota
of 62 patients with IBS and 46 controls
 2-fold decreased
in Bacteroidetes
(P .0001)

 1.5-fold reduction
of Bifidobacteria
(P .05)
 May produce
active serine
proteinase
inhibitors

 5% increased
level of Firmicutes
(P .0001)
Rajilic´-Stojanovic M, Biagi E et al. Global and Deep
Molecular Analysis of Microbiota Signatures in Fecal
Samples From Patients With Irritable Bowel Syndrome.
Gastroenterology 2011;141:1792–1801.
Diet
 Food Sensitivity--carbohydrate malabsorption
 FODMAPs (fermentable oligo-, di-, and
monosaccharides and polyols)
 Fermentation in distal small bowel/colon may cause
intestinal permeability and inflammation
 Gluten sensitivity
 Up to 70% of IBS patients who were HLA DQ2 positive
with negative work up for celiac disease reported
decreased symptoms after a gluten free diet compared
to 20% of HLA DQ2 negative patients
  Double blind placebo trial
 19 IBS patients on gluten-
P=0.02
free diet despite exclusion
of celiac disease
 15 controls
 2 slices of bread and a
muffin daily
P=0.001
P=0.03  No difference in HLA-DQ2
or DQ8, fecal lactoferrin,
CRP, intestinal
permeability or celiac
antibodies
Biesiekierski JR, Newnham ED. Gluten Causes
Gastrointestinal Symptoms in Subjects
Without Celiac Disease: A Double-Blind
Randomized Placebo-Controlled Trial. Am J
Gastro 2011;106:508-14.
 Food Patch Testing in IBS

 51 patients with IBS

 Most positive was garlic (12)

Stierstorfer MB, Sha CT et al. Food patch testing for irritable bowel syndrome. J Am Acad Dermatology 2012:1-8.
Psychosocial Associated Risk
 Prospective study of 2456 patients without IBS
 Over 15 months 3.5% developed IBS
 Independent predictors of IBS onset
 Anxiety (OR = 2.0; 95% CI 0.98–4.1)
 Sleep problems (OR = 1.6; 95% CI 0.8–3.2)
 Somatic symptoms (OR = 1.6; 95% CI 0.8–2.9)
 Other studies report association with abuse, anxiety,
depression, and phobias.

Nicholl BI, Halder SL. Psychosocial risk markers for new onset irritable bowel syndrome
– Results of a large prospective population-based study. Pain 2008;137:147–155.
  Global Improvement Score
(1-7)
1= much worse
4 =no change
7= much better

 Symptom Severity Score

(Five 100-point scales)
 Pain severity
 Pain frequency
 Severity of distention
 Dissatisfaction with bowel
habits
 Interference with quality of
life

 Adequate Relief
(over past week: yes/no)

 Quality of Life
(34 items, 0-100)
Kaptchuk T, Friedlander E, et al. Placebos without Deception: A Randomized
Controlled Trial in Irritable Bowel Syndrome. Plosone 2010:5(12).
Non-pharmacologic Therapies
 Fiber may be beneficial in IBS-C
 Lactose free, low flatulogenic, gluten-free or
FODMAPs diet
 Exercise, stress management (biofeedback, hypnosis,
psychotherapy)
 Therapeutic physician-patient relationship
Psychosocial Aspect
 Treating bowel-related symptoms is important, but
may not be sufficient, to impact overall HRQOL.
 Attempt to positively modify the cognitive
interpretation of IBS symptoms (ie, acknowledge and
address the emotional context in which symptoms
occur)
 Addressing symptom-related fears/concerns;
reassurance of benign nature of diagnosis
 Identifying and eliminating factors contributing to
vital exhaustion
 Gauge global symptom severity
BEST Questionnaire
 “How Bad are your bowel symptoms?”
 “Can you still Enjoy the things you used to enjoy?”
 “Do you feel like your bowel symptoms mean there’s
something Seriously wrong?”
 “Do your bowel symptoms make you feel Tense?”
 Scored 0-100
 Correlates well with the 34 question IBS-QOL
questionnaire

Spiegel BMR, Naliboff, Mayer E, et al. Development and initial validation of a

concise point-of-care IBS severity index: the 4-item BEST questionnaire.
Gastroenterology 2006;130:S1040
Antispasmodics
 May help with postprandial pain, gas, bloating and
fecal urgency on a prn basis
 Hyoscyamine, Dicyclomine
 anticholinergic/antimuscarinic
 Pinaverium, Mebeverine
 directly relax intestinal smooth muscle
 Peppermint oil
 may relax smooth muscle
 20-40% higher rate for response over placebo
 Cimetropium, Trimebutine
 Antidepressants
 May facilitate endogenous endorphin release
 Blockade of seratonin
 Enhance inhibitory pain pathways via blocking
norepinephrine reuptake
Meta-analysis of 14 studies
# patients % with persistent symptoms RR for persistence of NNT
(Treatment vs placebo) symptoms
TCA 575 41.4 vs 59.8 RR 0.68 4
(95% CI, 0.56 to 0.83)
SSRI 230 44.2 vs 70.9 RR 0.62 3.5
(95% CI, 0.45 to 0.87)

Ford AC, Talley NJ, et al. Efficacy of antidepressants and psychological therapies in
irritable bowel syndrome: systematic review and meta-analysis. Gut 2009;58:367–78
Probiotics
 Bifidobacterium infantis
 Bifidobacterium animalis
 Lactobacillus rhamnosus
 Lactobacillus plantarum
 Lactobacillus reuteri
 Bacillus coagulans
 Combinations
 e.g. VSL#3: Streptococcus thermophilus, B breve, B longum, B
infantis, L acidophilus, L plantarum, L paracasei, L
delbreuckii/bulgaricus
 Heterogenous studies, many with end points that are not
clinically applicable or compared with placebo.
Bifidobacterium infantis 35624 (Align)
• 362 Women with IBS
• Taken daily for 4
weeks
• Global Assessment
• “Please consider how you
felt in the past week in
regard to your IBS, in
particular your general
well-being, and
symptoms of abdominal
discomfort or pain,
bloating or distension
and altered bowel habit.
Compared to the way
you felt before beginning
the medication, have you
had adequate relief of
your IBS symptoms?”
Whorwell PJ, Altringer L, et al. Efficacy of an Encapsulated Probiotic Bifidobacterium
infantis 35624 in Women with Irritable Bowel Syndrome. Am J Gastroenterol 2006;101:1581–1590.
5-Hydroxytryptamine 3 Receptor
Antangonists
 May decreased pain via modulation of visceral afferent
activity
 Alosetron, Ondansetron, Granisetron, Cilansetron (FDA
application withdrawn)
 Alosetron (Lotronex) developed for IBS
 Reduces colonic motility and secretions
 Meta-analysis showed improvement in global symptoms
and abdominal pain, mostly in females with IBS-D
 Alosetron associated with:
 Severe constipation
 Idiosyncratic ischemic colitis (2/1000 by 3 months, 3/1000 by
6 months)
 Prescription restricted
Lubiprostone (Amitiza)
 Bicyclic fatty acid derived from prostaglandin E1
 Increases chloride transport
 ClC-2 chloride channel
 CFTR chloride channels via prostanoid receptor EP4?
 Approved for women with IBS-C at 8mcg BID (24 mcg
BID for chronic idiopathic constipation)
 Pregnancy test recommended in women capable of
becoming pregnant as safety has not been evaluated
Lubiprostone (Amitiza)
 1154 patients with IBS-C (92% female)
 “How would you rate your relief of IBS symptoms (abdominal discomfort/pain,
bowel habits, and other IBS symptoms) over the past week compared to how you
felt before you entered the study?”
 Responder if moderately or significantly better (6 or 7 on 7-point balanced scale)

• Responders in the lubiprostone

group (17.9%) was significantly higher
than that in the placebo group (10.1%;
P=0.001).
• Follow up study of 522 patients
showed benefits continued at 52
weeks.

Drossman DA, Chey WD. Clinical trial: Lubiprostone

in patients with constipationassociated irritable
bowel syndrome – results of two randomized,
placebo-controlled studies. Aliment Pharmacol Ther
2009;29:329–341.
Linaclotide (Linzess)

 Guanylate cyclase activation increases intracellular and extracellular cyclic guanosine

monophosphate
 Inhibition of afferent neurons
 Activation of Cystic Fibrosis Transmembrane conductance Regulator via phosphorylation by
Protein Kinase II
Linaclotide (Linzess)
• 804 IBS-C patients over
26 weeks (90% female)
• FDA approved 290 mcg
daily for IBS-C

Chey WD, Lembo AJ, et al. Linaclotide for Irritable Bowel

Syndrome With Constipation: A 26-Week, Randomized,
Double-blind, Placebo-Controlled Trial to Evaluate Effi
cacy and Safety. Am J Gastro 2012;Vol107:1702-12.
Rifaximin (Xifaxan)
 Nonabsorbable oral broad spectrum antibiotic
 TARGET 1 and 2
 1258 patients with IBS-D
 550 mg TID for 14 days
 Primary end point
 Adequate relief of global IBS symptoms for at least 2 of
the first 4 weeks after treatment
Rifaximin (Xifaxan)

 Adequate relief of global IBS symptoms: 40.7% vs. 31.7%

 Decreased bloating: 40% vs 30%
Pimentel M, Lembo A, et al. Rifaximin Therapy for Patients with Irritable
Bowel Syndrome without Constipation. N Engl J Med 2011;364:22-32.
 References
 Andrews EB , Eaton SC , Hollis KA et al. Prevalence and demographics of irritable bowel
syndrome: results from a large web-based survey. Aliment Pharmacol Ther 2005;22: 935–42 .
 Biesiekierski JR, Newnham ED. Gluten Causes Gastrointestinal Symptoms in Subjects
Without Celiac Disease: A Double-Blind Randomized Placebo-Controlled Trial. Am J Gastro
2011;106:508-14.
 Brandt LJ, Chey WD, et al. An Evidence-Based Systematic Review on the Management of
Irritable Bowel Syndrome. The Am J Gastroenterology 2009; Volume 104 supplement 1.
 Chey WD, Lembo AJ, et al. Linaclotide for Irritable Bowel Syndrome With Constipation: A 26-
Week, Randomized, Double-blind, Placebo-Controlled Trial to Evaluate Effi cacy and Safety.
Am J Gastro 2012;Vol107:1702-12.
 Dorn SD, Palsson OS. Increased colonic pain sensitivity in irritable bowel syndrome is the
result of an increased tendency to report pain rather than increased neurosensory sensitivity.
Gut 2007;56:1202–09
 Drossman DA, Chey WD. Clinical trial: Lubiprostone in patients with constipation associated
irritable bowel syndrome – results of two randomized, placebo-controlled studies. Aliment
Pharmacol Ther 2009;29:329–341.
 Ford AC, Talley NJ, et al. Efficacy of antidepressants and psychological therapies in irritable
bowel syndrome: systematic review and meta-analysis. Gut 2009;58:367–78
 Gonsalkorale WM, Perrey C. Interleukin 10 genotypes in irritable bowel syndrome: evidence
for an inflammatory component? Gut 2003;52:91–93.
 Kaptchuk T, Friedland er E, et al. Placebos without Deception: A Randomized Controlled Trial
in Irritable Bowel Syndrome. Plosone 2010:5(12).
 Kruis W, Thieme C, Weinzierl M, et al. A diagnostic score for the irritable bowel syndrome. Its
value in the exclusion of organic disease. Gastroenterology 1984;87:1–7.
 References (continued)
 Lovell RM, Ford AC. Global Prevealence of and Risk Factors for Irritable Bowel Syndrome: a
Meta-analysis. Clinical Gastroenterology and Hepatology 2012:10(7); 712-21.
 Manning AP, Thompson WG. Towards positive diagnosis of the irritable bowel. BMJ 1978;2:653-
4.
 Nicholl BI, Halder SL. Psychosocial risk markers for new onset irritable bowel syndrome –
Results of a large prospective population-based study. Pain 2008;137:147–155.
 Pimentel M, Lembo A, et al. Rifaximin Therapy for Patients with Irritable Bowel Syndrome
without Constipation. N Engl J Med 2011;364:22-32.
 Rajilic´-Stojanovic M, Biagi E et al. Global and Deep Molecular Analysis of Microbiota
Signatures in Fecal Samples From Patients With Irritable Bowel Syndrome. Gastroenterology
2011;141:1792–1801.
 Saito YA. The Role of Genetics in IBS. Gastroenterol Clin N Am 2011(40):45–67.
 Salonen A, de Vos WM et al. Gastrointestinal microbiota in irritable bowel syndrome: present
state and perspectives. Microbiology (2010), 156, 3205–15.
 Sheehan J, Gaman A et al. Pooled analysis of brain activity in irritable bowel syndrome and
controls during rectal balloon distension. Neurogastroenterol Motil (2011) 23, 336–e158.
 Spiegel BMR, Naliboff, Mayer E, et al. Development and initial validation of a concise point-of-
care IBS severity index: the 4-item BEST questionnaire. Gastroenterology 2006;130:S1040
 Whorwell PJ, Altringer L, et al. Efficacy of an Encapsulated Probiotic Bifidobacterium
 infantis 35624 in Women with Irritable Bowel Syndrome. Am J Gastroenterol 2006;101:1581–
1590.
Dr Arun Aggarwal
MD